There is an urgent need for a new glucose sensor that is: (1) highly reliable and continuous; (2) capable of automatic function, independent of user initiative, to warn of hypoglycemia; and (3) acceptable to users. We have an implantable electrochemical glucose sensor that can potentially meet this need. A prototype of this sensor has operated continuously as a central venous implant in dogs for over 100 days without the need for recalibration and now in humans for over one year. This achievement still represents the published world's record for implanted glucose sensor longevity. For reasons of safety, we are designing a tissue glucose sensor for long-term use in humans. The implant will include the sensor, electronics and telemetry, antenna, and battery. Glucose signals will be transmitted to an external receiver resembling a beeper that will display the actual glucose value and function as a hypoglycemia alarm. Our recent studies have focused on developing a complete understanding of the tissue sensor response to blood glucose. The working hypothesis is: "A useful analytical relationship exists between the signal of sensors implanted in tissue and blood glucose concentration." We have: defined sensor performance requirements, developed methods of sensor fabrication, implanted sensors in a well-defined hamster model, established novel confocal microscopy methods for non-destructive visualization of the tissue/sensor interface, and modeled sensor response. We will extend our studies by implanting sensors in pigs and carry out extensive analysis of sensor system dynamics, including development of a method for sensor recalibration, further documentation of implant biocompatibility, and establishment of system reliability. These studies will be carded out in addition to our continuing studies in hamsters and diabetic rats. These studies set the stage for trials in humans.